The proposed research project is designed to investigate the mechanism and distribution of action of delta-9-tetrahydrocannabinol (THC - a major psychoactive constituent of marihuana) in the rodent brain. THC is a potent excitatory neuromodulator of hippocampal activity in picomolar concentrations and appears to act at membrane-active estrogen receptors in hippocampus. We propose to examine this hypothesis and determine which other brain areas display this neuromodulation. The role of membrane-acting estrogen receptors will be studied using estrogen antagonists to see if they can also block the THC effect in hippocampal slice preparations. This hypothesis will also be tested by castrating male rats and priming them with heterotypic or homotypic gonadal steroids, a treatment that alters the cellular response to applied estrogen. If the membrane-acting estrogen receptor is involved, we expect to see a THC effect only in the group primed with the heterotypic steroid. Brain localization will be determined electrophysiologically following an autoradiography uptake study to identify regions concentrating the labeled THC. This data will also allow us to evaluate the nature of the estrogen receptor hypothesis by comparing the distribution of THC neuromodulation to the known distribution of estrogen cytosol receptors. Since an estrogen receptor appears to mediate the THC effect, we shall examine the nature of the THC neuromodulation in hippocampus of female rats tested in various stages of the estrous cycle. Other localization studies will attempt to determine if cholinergic systems are preferentially affected by THC and will examine the cellular locus of THC neuromodulation. The demonstrated hippocampal THC neuromodulation may be related to the human effects of THC intoxication on learning, memory and emotionality. The role of THC in cortical regions may similarly be related to the cognitive and perceptual alterations noted in human experience with this drug.